Almost 70 years ago the human cutaneous active vasodilator system was first described; however, its mechanisms remain unclear today. The long term goal of this project is to define the physiological mechanisms that effect cutaneous active vasodilation during thermoregulatory reflex responses to hyperthermia. This will contribute to our understanding of the role of the cutaneous circulation in adaptation to hot environments and understanding the increased morbidity and mortality of persons with limited cardiac output, including the aged and those with cardiac disease. An enhanced understanding of the cutaneous circulation may reduce mortality in the growing patient population that receives numerous pharmacological therapies that may predispose them to iatrogenic heat intolerance, heat stroke, and death. The following specific aims will be explored. 1) Determine whether bradykinin is involved in cutaneous active vasodilation during heat stress. 2) Clarify whether nitric oxide (NO) levels increase and cause cutaneous active vasodilation during heat stress or whether NO levels remain constant and functions as a permissive factor during heat stress. 3) Determine whether the nitric oxide required for cutaneous active vasodilation during heat stress is produced by endothelial nitric oxide synthase (eNOS) or by neuronal nitric oxide synthase (nNOS). 4) Determine the role of vasoactive intestinal polypeptide (VIP) in cutaneous active vasodilation during heat stress. 5) Determine the role of cAMP in cutaneous active vasodilation during heat stress. 6) Determine the role of cGMP in cutaneous active vasodilation during heat stress. Studies will be done in healthy humans. Intradermal microdialysis will be used to treat small areas of forearm skin with specific pharmacological agents to manipulate the bradykinin, nitric oxide, VIP, and second messenger systems. Laser-Doppler flowmetry will monitor skin blood flow responses during normothermia and hyperthermia at both drug-treated, experimental sites, and at adjacent untreated, control sites. In addition intradermal microdialysis will be combined with measurements of bioavailable NO by hemoglobin-trapping to define further how the NO system functions in cutaneous active vasodilation.